Lorea, Cláudia F

Significance RBM28 is a human protein essential for proper assembly of the large ribosomal subunit, crucially enabling synthesis of all cellular proteins. Defects in RBM28 cause rare ribosomopathies: alopecia, neurological defects, and endocrinopathy (ANE) syndrome. We investigated an ANE syndrome patient with a clinical presentation consistent with the definition of ANE syndrome but possessing differing genetic variants and molecular pathology. We find one inherited allele is null, clarifying that ANE syndrome is not caused by RBM28 haploinsufficiency, while the other inherited allele retains enough function to enable survival but preclude proper development. Our results define an underlying pathology of ANE syndrome, further delineating an emerging class of assembly factor ribosomopathies and underscoring the importance of nucleolar processes in human health.

Abstract Context Genetic variants in SLC16A2, encoding the thyroid hormone transporter MCT8, can cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency. The C-terminal domain of MCT8 is poorly conserved, which complicates prediction of the deleteriousness of variants in this region. We studied the functional consequences of 5 novel variants within this domain and their relation to the clinical phenotypes. Methods We enrolled male subjects with intellectual disability in whom genetic variants were identified in exon 6 of SLC16A2. The impact of identified variants was evaluated in transiently transfected cell lines and patient-derived fibroblasts. Results Seven individuals from 5 families harbored potentially deleterious variants affecting the C-terminal domain of MCT8. Two boys with clinical features considered atypical for MCT8 deficiency had a missense variant [c.1724A>G;p.(His575Arg) or c.1796A>G;p.(Asn599Ser)] that did not affect MCT8 function in transfected cells or patient-derived fibroblasts, challenging a causal relationship. Two brothers with classical MCT8 deficiency had a truncating c.1695delT;p.(Val566*) variant that completely inactivated MCT8 in vitro. The 3 other boys had relatively less-severe clinical features and harbored frameshift variants that elongate the MCT8 protein [c.1805delT;p.(Leu602HisfsTer680) and c.del1826-1835;p.(Pro609GlnfsTer676)] and retained ~50% residual activity. Additional truncating variants within transmembrane domain 12 were fully inactivating, whereas those within the intracellular C-terminal tail were tolerated. Conclusions Variants affecting the intracellular C-terminal tail of MCT8 are likely benign unless they cause frameshifts that elongate the MCT8 protein. These findings provide clinical guidance in the assessment of the pathogenicity of variants within the C-terminal domain of MCT8.